HexamollDINCH is an important alternative to phthalate plasticizers. Although regulatory reviews ... more HexamollDINCH is an important alternative to phthalate plasticizers. Although regulatory reviews have not identified any potential hazards even in sensitive populations, an in vitro study by Campioli et al. (2015) suggested HexamollDINCH might alter fat storage in adipocytes resulting in obesity. To evaluate this hypothesis, data from studies with HexamollDINCH were reviewed for evidence of deposition in fat, changes in body weight, or changes in serum chemistry reflecting altered metabolic status. Body weights of F1 and F2 pups in a two-generation study did not differ from controls even at 1000 mg HexamollDINCH/kg body weight. Mean relative liver weights from the 1000 and 300 mg/kg bw groups were increased, but without histopathologic changes. Triglyceride and cholesterol levels in serum were not affected. In addition, subchronic and chronic studies in rats did not give evidence of an obesogenic effect. Radioactivity from 20 or 1000 mg/kg bwC-labelled HexamollDINCH dosed orally rem...
The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their poten... more The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g...
Phthalate esters can be divided into three general categories based on size. These categories are... more Phthalate esters can be divided into three general categories based on size. These categories are low-MW esters used as solvents in cosmetics or as plasticizers of cellulose acetate polymers, mid-MW esters used as solvents in some PVC products but only in combination with other plasticizers in floor coverings, or as a solvent or plasticizer in the cosmetic and pharmaceutical industries, and high-MW esters used as plasticizers of PVC for wire and cable coverings, medical products, and other consumer products. Phthalate esters are data-rich for effects in laboratory animals, having been the focus of much research because of their effects on the biochemistry of liver cells, the effects on the testes, and the effects on the development of laboratory animals. All phthalate esters have little or no toxicity following single (acute) exposures. These substances are not dermal sensitizers, but may produce minor skin irritation with prolonged exposure to the neat chemical. Long-term hazards from short-term exposures are either minimal or reversible because many long-term effects are observed only following continuous exposure. Long-term effects such as liver cancer only occur in laboratory animals following lifetime or near lifetime exposure to doses of >100 mg kg-1 d-1 of high-MW esters. Cancer is thought to occur through a mechanism that involves biochemical changes in the liver cells of rats and mice. These biochemical changes are not seen in primates. As a result, scientists do not regard humans to be at risk of cancer from exposure to phthalate esters. Reproductive toxicity or developmental effects in the offspring of laboratory animals exposed to mid-MW phthalates during gestation have been reported. Reproductive toxicity is the result of damage to the testes causing lack of sperm production. It is not known if such effects occur in humans, but adult primates have been resistant to the effects seen in adult rodents. Developmental effects can also occur with high exposure to mid-MW esters. The effects include incomplete skeletal formation in the head, spinal cord, tail, and ribs. In addition, male rats demonstrate incomplete formation of the urogenital tract. It is not known if primates or humans are also susceptible to these effects, and the mechanism in laboratory animals is unknown. Exposure to phthalate esters is not thought to cause respiratory diseases such as asthma because these substances are hypoallergenic, but some have tried to associate exposure with an increased sensitivity to respiratory allergens. Sufficient data are lacking to make such a correlation. Phthalate esters are not neurotoxic. In evaluating the concern for humans, many principles of toxicology are discussed to provide the reader with sufficient understanding of species extrapolation. Primates are not as sensitive to phthalate esters as are rodents. There may be a variety of reasons for this lack of sensitivity, for example, lower absorption and different metabolic pathways. There are also intrinsic differences in the responses of primate and human cells to the biochemical effects of phthalate esters. While this difference relates directly to the likelihood of cancer, it may also impact the sensitivity to other effects seen in animals. Thus, predicting the effects in humans must convey some level of uncertainty.
n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern... more n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern for neurotoxicity as part of the Multisubstance Rule for the Testing of Neurotoxicity. The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. Transient signs of sedation and...
h i g h l i g h t s • Repeated infusion of Hexamoll ® DINCH ® for 4 weeks did not result in syste... more h i g h l i g h t s • Repeated infusion of Hexamoll ® DINCH ® for 4 weeks did not result in systemic toxicity. • 300 mg/kg bw/day, the highest dose level that could be tested was identified as NOAEL. • Effects seen are most likely related to exceeding intravasal solubility of the test substance. • Study supports the risk-/benefit assessment for Hexamoll ® DINCH ® based medical devices.
This chapter presents information on esters of mono-, di-, and tricarboxylic acids with monoalcoh... more This chapter presents information on esters of mono-, di-, and tricarboxylic acids with monoalcohols from 1 to over 10 carbons in either a straight chain or branched configuration. In general, the properties (chemical and functional) change with the carbon length of the alcohol. Properties shift from higher water solubility and lower boiling point to lower water solubility and higher boiling point for esters of a particular acid group. There is insufficient information to conclude that the carbon length of the acid group influences the properties significantly. Also included are esters of the trialcohol, glycerol, with monocarboxylic acids. These substances are included for the sake of completeness. All esters are subject to hydrolysis, especially enzymatic hydrolysis. Most esters in biotic systems hydrolyze primarily to the carboxylic acid and alcohol. There are some exceptions such as esters of phthalic acid that form relatively stable monoesters in biotic systems, which can be further oxidized. The uses of various esters are reviewed below and they vary with the acid. The simple aliphatic esters of benzoic acid are liquids that are used as solvents, flavors, or perfumes. Benzyl benzoate is used as a miticide or as a plasticizer. In general, these compounds have a low order of toxicity. The primary effects expected from the ingestion of moderate amounts of benzoates are gastrointestinal (GI) irritation, gastric pain, nausea, and vomiting. Available data indicate a low order of skin absorbability, and the undiluted materials may be either slight or moderate skin irritants. In rabbits, the degree of skin irritation caused by alkyl benzoates increases with an increase in molecular weight. The salicylates are used as flavorants, perfumes, or analgesics. The most commonly used member of this class of compounds is methyl salicylate. Ingestion of relatively small quantities of methyl salicylate may cause severe, rapid-onset salicylate poisoning. The lower alkyl esters of p- or 4-hydroxybenzoic acid (C1–C4), also named the methyl-, ethyl-, propyl-, and butyl parabens, are high-boiling liquids that decompose on heating. They are widely used in the food, cosmetic, and pharmaceutical industries as preservatives, bacteristats, and fungistats. Parabens also have been used therapeutically in the treatment of moniliasis, a Candida albicans infection. By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The lower paraben homologues have low potential for acute or chronic systemic toxicity and are therefore approved as human food additives. Cinnamates (phenyl acrylates and phenylpropenoic acid esters) are mainly used as fragrances in the perfume industry. Cinnamates appear to have low to moderate toxicity in mammals. In humans, dermal exposure to allyl cinnamate may cause skin irritation. Some p-aminobenzoic acid (PABA) esters occur naturally, because the free compound, PABA, that is utilized for their synthesis, is an intricate part of the vitamin B complex. PABA esters exhibit a low order of acute toxicity in experimental animals. In humans, cases of methemoglobinemia after topical benzocaine or procaine use have been reported. Sunscreen agents containing PABA esters may occasionally produce allergic photosensitization. The o-aminobenzoates (anthranilates) are less irritating and less likely to cause sensitization than do the p-aminobenzoates, but have less therapeutic usefulness. They are used in some sunscreen lotions. Anthranilates have low toxicity potential. Long-chain fatty acids of glycerides may be replaced by one or more acetyl groups to produce mono-, di-, or triacetin. Acetins, propionates, and butyrates serve as food additives, solvents or plasticizers, and surface-active agents. Available evidence indicates that these agents exhibit a low order of toxicity. Normally, no irritant effects occur upon inhalation or direct dermal contact. The higher glycerides of fatty acids with odd-numbered carbon chains (C5–C11) are found naturally in very small quantities in diverse organisms, and the even-numbered (C12–C24) esters are common nutritional constituents. They are used as emulsifiers for foods, industrial raw materials, or nonacid detergent components. Some toxicity data are available for the C5 and C8 compounds. The even-numbered C12–C18 glycerides are nontoxic. Little toxicological information is available about resorcinol ester compounds. Gallates are chemically trihydroxybenzoic acid esters. They serve generally as antioxidants, and the propyl, octyl, and dodecyl gallates have been approved as food additives. The gallates exhibit low acute and chronic toxicity in experimental animals. The bulk of evidence suggests that they are not carcinogenic or teratogenic. Oxalates, malonates, glutarates, and succinates are high-flash, high-boiling fluids. Oxalates and malonates are mainly used as solvents for resins or as chemical intermediates. The general industrial use of these materials has…
The effect of whole cigarette smoke exposure on bone-marrow sister-chromatid exchanges (SCEs) was... more The effect of whole cigarette smoke exposure on bone-marrow sister-chromatid exchanges (SCEs) was studied in B6C3F1 mice. Animals were exposed nose-only to 10% (v/v) cigarette smoke 5 days/week for 2 weeks. Four dose levels of cigarette smoke (1, 4, 9 and 18 exposures/day) were studied using 2 cigarette types, Kentucky reference 3A1 (3A1) and American Blend (AB). A single exposure represented approximately 1 cigarette. A dose-dependent increase in SCEs was observed for both the 3A1 and AB cigarettes at dose levels which had no effect on bone-marrow cell-replication kinetics. These findings represent the first demonstration of a dose-responsive increase in cigarette smoke-induced SCEs in a rodent model system.
Regulatory toxicology and pharmacology : RTP, 2011
In 1998, the National Toxicology Program concluded that inhalation exposure to tetrahydrofuran re... more In 1998, the National Toxicology Program concluded that inhalation exposure to tetrahydrofuran resulted in increased incidences of renal adenomas and carcinomas (combined) in male F344 rats and of hepatocellular adenomas and carcinomas (combined) in female B6C3F1 mice. In the present paper, the bioassay results and additional information are evaluated using the IPCS/ILSI Mode of Action/Human Relevance Framework to determine if the data are sufficient to describe the possible mode(s) of action (MOA) underlying the reported results for the rat renal tumor and to determine if any of these modes of action could be operative in humans. Preliminary analysis of the rat renal tumor data and related information suggested that a MOA could be described, but questions remained concerning the role that chronic progressive nephropathy (CPN) may play in the development of the lesions. In 2009, a Pathology Working Group concluded that the rat renal lesions resulted primarily from regenerative proce...
Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protec... more Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protection Agency (US EPA) for testing under the Multi-Substance Rule for the Testing of Neurotoxicity (US EPA, 1993) using schedule-controlled operant behavior (SCOB) to determine if subchronic exposure to MiBK vapor had the potential to alter behavior as an indicator of neurotoxicity. Food-restricted and ad libitum-fed Sprague-Dawley male rats were exposed to 0, 250, 750, or 1500 ppm MiBK for 6 h/day, 5 d/wk for 13 weeks. SCOB testing of food-restricted animals, using a multiple fixed ratio (FR)/fixed interval (FI) schedule (FR20:FI120), was conducted prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. SCOB testing was also evaluated for two weeks following the cessation of exposures. Ad libitum-fed animals were included to assess systemic effects using routine indicators such as changes in body weight, f...
At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, particip... more At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Rep...
Following oral administration of 1,6-[14C]diaminohexane (hexamethylenediamine, HMDA) to male Fisc... more Following oral administration of 1,6-[14C]diaminohexane (hexamethylenediamine, HMDA) to male Fischer-344 rats, approx. 20% of the administered dose was recovered as 14CO2 after 72 h. Urinary and fecal excretion accounted for 47% and 27% of the administered radioactivity, respectively. Of several tissues examined, the highest concentrations of residual radioactivity were found in the prostate at 24 and 72 h post-administration. Daily administration of HMDA (200 mg/kg/day) by gavage to pregnant female rats for 2 weeks starting on gestation day 0 did not affect litter size in these animals.
Regulatory toxicology and pharmacology : RTP, 2010
Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incide... more Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incidences of renal tumors in male F344/N rats reported in a 2-year carcinogenicity study by the National Toxicology Program (NTP). A Pathology Working Group (PWG) was commissioned to conduct an independent review of the kidney slides from this bioassay (along with two subchronic studies) to assess renal changes in light of recent scientific work on pathogenesis of pre-neoplastic and neoplastic lesions in rat kidney. PWG pathologists confirmed the NTP assessment that adenomas were non-statistically increased in animals exposed to the highest level of THF. However, when pre-neoplastic and neoplastic lesions were combined, there was no difference between control and THF-exposed groups. Also, the majority of these proliferative lesions were in rats with severe chronic progressive nephropathy (CPN). Accordingly, the PWG concluded that renal lesions in the control and THF-exposed groups resulted pr...
BACKGROUND: The plasticizer di-2-ethylhexyl phthalate (DEHP) is a common component in medical pla... more BACKGROUND: The plasticizer di-2-ethylhexyl phthalate (DEHP) is a common component in medical plastics. There is motivation to replace this component; however, DEHP is necessary to prevent excessive hemolysis in stored red blood cells (RBCs). Our objective is to evaluate a candidate replacement plasticizer (Hexamoll, di-isononyl cyclohexane-1,2-dicarboxylic acid [DINCH], BASF Corp.) compared to DEHP in an in vitro feasibility study. We hypothesize that the candidate will provide at least equivalent protection against hemolysis for RBCs stored for 42 days and periodic mixing of RBCs will add additional protection against hemolysis. STUDY DESIGN AND METHODS: Whole blood was collected into citrate-phosphate-dextrose; combined into pools of 2 ABO identical whole blood units; and divided, leukoreduced, centrifuged, and separated into plasma and RBCs. Additive solution was added, and the RBCs were stored for 42 days at 1 to 6°C. In three parts of this study, split pools were paired as DINCH-polyvinyl chloride (PVC) with weekly mixing versus DINCH-PVC with no mixing, DINCH-PVC mixed versus DEHP-PVC no mix, and DINCH-PVC versus DEHP-PVC with neither mixed. A standard panel of in vitro RBC characteristics was determined on Days 0 and 42. RESULTS: Mixing DINCH-PVC weekly improved Day 42 hemolysis (0.36 Ϯ 0.07% vs.0.56 Ϯ 0.15%, p = 0.002), and mixed DINCH-PVC bags were noninferior to unmixed DEHP-PVC bags (p Յ 0.05). DINCH-PVC bags stored without weekly mixing were inferior to unmixed DEHP-PVC bags for hemolysis on Day 42, although no individual bag exceeded 0.8% hemolysis. CONCLUSION: Periodic mixing of RBCs stored in DINCH-PVC provides additional protection against hemolysis. Unmixed DINCH-PVC bags were inferior to DEHP-PVC bags for prevention of hemolysis, but remain a candidate for replacement DEHP in RBC storage bags. ABBREVIATIONS: BTHC = n-butyl tri-n-hexyl citrate; DEHP = di-2-ethylhexyl phthalate; DINCH = di-isononyl cyclohexane-1,2-dicarboxylic acid; LOQ = limits of quantification; MCV = mean corpuscular volume; MINCH = mono-isononyl-1,2cyclohexane dicarboxylic acid.
Bronchial asthma is mediated, in part, by the immunoregulatory cytokines interleukins 4 and 13 (I... more Bronchial asthma is mediated, in part, by the immunoregulatory cytokines interleukins 4 and 13 (IL-4 and IL-13). These cytokines stimulate IgE synthesis that in turn is associated with airway hyper-responsiveness. Compounds that stimulate IgE synthesis and elicit bronchial reactivity are generally considered to be respiratory sensitizers. Recently, it has been hypothesized that exposure to phthalates may contribute to childhood asthma. To address this question, di-(2-ethylhexyl) phthalate (DEHP) was tested using a protocol adapted from work by Dearman that involves topical application (and challenge) of test substances to mice followed by measurements of total serum IgE. In addition, auricular lymph nodes were harvested for measurement of IL-4 and IL-13 proteins and their corresponding messenger RNAs. Because skin absorption of high molecular weight phthalates is limited, liver weight increase, a measure of peroxisomal proliferation, was monitored to assure that internal dosing had been achieved. ELISA and RNAse protection assays demonstrated that DEHP treatment did not significantly affect IgE, IL-4, or IL-13 levels. Similarly, IL-4 and IL-13 mRNA levels were not elevated. In contrast, all of these were significantly elevated by trimellitic anhydride (TMA), a respiratory sensitizer used as the positive control in this assay. Liver weights were significantly elevated by DEHP, providing evidence of sufficient percutaneous absorption to induce physiological responses. To extend these observations, three other commercial phthalate ester plasticizers, di-isononyl phthalate (DINP), di-isohexyl phthalate (DIHP), and butyl benzyl phthalate (BBP), were assessed using the same protocol. As above, ELISA and RNAse protection assays showed that IgE, IL-4, and IL-13 proteins, and IL-4 and IL-13 mRNAs in the phthalate-treated animals were all at levels similar to that of control values. The positive control, TMA, produced large, statistically significant increases in all parameters, demonstrating responsiveness of the assay. Another control, dinitrochlorobenzene (DNCB), a contact sensitizer, also responded as expected, producing smaller but statistically significant increases in IgE and in mRNA for IL-4 and IL-13 but not in the levels of these cytokines.
Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm di(2-ethylhexyl)phthalate (DE... more Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at weeks 26, 52, 78, and 104 from 10 animals per sex per group. Survival was slightly but not statistically reduced for rats receiving 12,500 ppm DEHP. Body weights and food consumption were significantly reduced for rats receiving the highest dose level of DEHP and occasionally for the male 2500-ppm group. BUN and albumin were significantly higher and globulin lower at nearly every sampling interval for the 12,500-ppm group compared with the controls. There was an increase in the mean activities of AST and ALT at 104 weeks, but no statistically significant differences were seen. Erythrocyte count, hemoglobin, and hematocrit values for the 12,500-ppm group were significantly lower than controls at nearly every sampling interval. No other differences in hematology were seen. No toxicologically significant changes were observed in urinalysis. At termination, relative lung weights for the 2500-and 12,500-ppm male groups of rats were significantly higher than for the controls. Absolute and relative liver and kidney weights for the 2500-and 12,500-ppm male rats, and liver weights for 12,500-ppm female rats were higher compared with the controls. Absolute and relative testes weights for the 12,500-ppm male rats were lower compared with the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately and correlated with the induction of peroxisomal enzyme activity (David et al., 1999). A dose level of 500 ppm was the NOEL for peroxisome proliferation. Bilateral aspermatogenesis in the testes, castration cells in the pituitary gland, spongiosis hepatis, and pancreatic acinar cell adenoma were observed for 12,500ppm male rats. Aspermatogenesis and spongiosis hepatis were observed for 2500-ppm male rats, and aspermatogenesis was seen at 500 ppm. DEHP exposure exacerbated age-, species-or strainrelated lesions such as mineralization of the renal papilla and chronic progressive nephropathy in male rats. Kupffer cell pigmentation and renal tubule pigmentation were seen in male and female 12,500-ppm rats. The increased incidence of spongiosis hepatis correlated with increased palmitoyl CoA oxidase activity, but the incidence of pancreatic acinar cell adenoma was increased only at the highest dose level of 12,500 ppm. These lesions, although typical of those seen with other peroxisome proliferators, may respond differently depending on the potency of the peroxi-some proliferator. A dose level of 500 ppm (28.9-36.1 mg/kg/day) was considered to be theNOAEL.
This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver... more This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver with tumor incidence, to provide more information on the relationship between these events following chronic exposure. Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm DEHP, and B6C3F 1 mice were treated with 0, 100, 500, 1500, or 6000 ppm DEHP in the diet for up to 104 weeks. Additional groups of rats and mice received the highest concentration for 78 weeks and then the control diet for an additional 26 weeks (recovery groups). Animals were terminated at weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA oxidation activity and higher liver-to-body weight ratios were observed for the 2500-and 12,500-ppm groups of rats, and for the 500-, 1500-, and 6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation activity was evident in the recovery group, and relative liver weights were near control levels following recovery. No hepatic cell proliferation was detected at Weeks 79 or 105 in either species although preliminary data indicated that cell proliferation did occur within the first 13 weeks of exposure. A significantly higher incidence of hepatocellular tumors was only observed for the 2500-and 12,500-ppm group and its recovery group of rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group of mice. The tumor incidences were reduced for the recovery groups compared with the groups fed DEHP continuously for 104 weeks. The data indicate that high levels of peroxisome proliferation and hepatomegaly are associated with DEHP hepatocarcinogenesis in rodent liver, and that the tumorigenic process may be arrested by cessation of DEHP treatment, suggesting that extended treatment with DEHP acts to promote tumor growth.
Fischer-344 rats treated with 12,500 ppm (728 and 879 mg/kg/d for male and females, respectively)... more Fischer-344 rats treated with 12,500 ppm (728 and 879 mg/kg/d for male and females, respectively) and B6C3F1 mice treated with 6,000 ppm (1,227 and 1,408 mg/kg/d, respectively) di(2-ethylhexyl)phthalate (DEHP) in the diet for 78 weeks were allowed to recover for an additional 26 weeks on control diet. Blood was analyzed at weeks 78 and 104 from 10 animals per sex per group; animals were sacrificed at weeks 79 and 105 for histopathologic examination. The results are compared with data from animals continuously exposed to these dietary levels for 104 weeks (10, 11). Body weights and food consumption were measured monthly. BUN, albumin, and globulin that were significantly different for rats exposed to DEHP throughout 104 weeks, were comparable to controls for the recovery group. Reversibility of chronic effects on erythrocyte count, hemoglobin, and hematocrit values was apparent only for female rats. Chronic exposure demonstrated effects on liver, kidney, and testes weights. All organ...
HexamollDINCH is an important alternative to phthalate plasticizers. Although regulatory reviews ... more HexamollDINCH is an important alternative to phthalate plasticizers. Although regulatory reviews have not identified any potential hazards even in sensitive populations, an in vitro study by Campioli et al. (2015) suggested HexamollDINCH might alter fat storage in adipocytes resulting in obesity. To evaluate this hypothesis, data from studies with HexamollDINCH were reviewed for evidence of deposition in fat, changes in body weight, or changes in serum chemistry reflecting altered metabolic status. Body weights of F1 and F2 pups in a two-generation study did not differ from controls even at 1000 mg HexamollDINCH/kg body weight. Mean relative liver weights from the 1000 and 300 mg/kg bw groups were increased, but without histopathologic changes. Triglyceride and cholesterol levels in serum were not affected. In addition, subchronic and chronic studies in rats did not give evidence of an obesogenic effect. Radioactivity from 20 or 1000 mg/kg bwC-labelled HexamollDINCH dosed orally rem...
The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their poten... more The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g...
Phthalate esters can be divided into three general categories based on size. These categories are... more Phthalate esters can be divided into three general categories based on size. These categories are low-MW esters used as solvents in cosmetics or as plasticizers of cellulose acetate polymers, mid-MW esters used as solvents in some PVC products but only in combination with other plasticizers in floor coverings, or as a solvent or plasticizer in the cosmetic and pharmaceutical industries, and high-MW esters used as plasticizers of PVC for wire and cable coverings, medical products, and other consumer products. Phthalate esters are data-rich for effects in laboratory animals, having been the focus of much research because of their effects on the biochemistry of liver cells, the effects on the testes, and the effects on the development of laboratory animals. All phthalate esters have little or no toxicity following single (acute) exposures. These substances are not dermal sensitizers, but may produce minor skin irritation with prolonged exposure to the neat chemical. Long-term hazards from short-term exposures are either minimal or reversible because many long-term effects are observed only following continuous exposure. Long-term effects such as liver cancer only occur in laboratory animals following lifetime or near lifetime exposure to doses of >100 mg kg-1 d-1 of high-MW esters. Cancer is thought to occur through a mechanism that involves biochemical changes in the liver cells of rats and mice. These biochemical changes are not seen in primates. As a result, scientists do not regard humans to be at risk of cancer from exposure to phthalate esters. Reproductive toxicity or developmental effects in the offspring of laboratory animals exposed to mid-MW phthalates during gestation have been reported. Reproductive toxicity is the result of damage to the testes causing lack of sperm production. It is not known if such effects occur in humans, but adult primates have been resistant to the effects seen in adult rodents. Developmental effects can also occur with high exposure to mid-MW esters. The effects include incomplete skeletal formation in the head, spinal cord, tail, and ribs. In addition, male rats demonstrate incomplete formation of the urogenital tract. It is not known if primates or humans are also susceptible to these effects, and the mechanism in laboratory animals is unknown. Exposure to phthalate esters is not thought to cause respiratory diseases such as asthma because these substances are hypoallergenic, but some have tried to associate exposure with an increased sensitivity to respiratory allergens. Sufficient data are lacking to make such a correlation. Phthalate esters are not neurotoxic. In evaluating the concern for humans, many principles of toxicology are discussed to provide the reader with sufficient understanding of species extrapolation. Primates are not as sensitive to phthalate esters as are rodents. There may be a variety of reasons for this lack of sensitivity, for example, lower absorption and different metabolic pathways. There are also intrinsic differences in the responses of primate and human cells to the biochemical effects of phthalate esters. While this difference relates directly to the likelihood of cancer, it may also impact the sensitivity to other effects seen in animals. Thus, predicting the effects in humans must convey some level of uncertainty.
n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern... more n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern for neurotoxicity as part of the Multisubstance Rule for the Testing of Neurotoxicity. The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. Transient signs of sedation and...
h i g h l i g h t s • Repeated infusion of Hexamoll ® DINCH ® for 4 weeks did not result in syste... more h i g h l i g h t s • Repeated infusion of Hexamoll ® DINCH ® for 4 weeks did not result in systemic toxicity. • 300 mg/kg bw/day, the highest dose level that could be tested was identified as NOAEL. • Effects seen are most likely related to exceeding intravasal solubility of the test substance. • Study supports the risk-/benefit assessment for Hexamoll ® DINCH ® based medical devices.
This chapter presents information on esters of mono-, di-, and tricarboxylic acids with monoalcoh... more This chapter presents information on esters of mono-, di-, and tricarboxylic acids with monoalcohols from 1 to over 10 carbons in either a straight chain or branched configuration. In general, the properties (chemical and functional) change with the carbon length of the alcohol. Properties shift from higher water solubility and lower boiling point to lower water solubility and higher boiling point for esters of a particular acid group. There is insufficient information to conclude that the carbon length of the acid group influences the properties significantly. Also included are esters of the trialcohol, glycerol, with monocarboxylic acids. These substances are included for the sake of completeness. All esters are subject to hydrolysis, especially enzymatic hydrolysis. Most esters in biotic systems hydrolyze primarily to the carboxylic acid and alcohol. There are some exceptions such as esters of phthalic acid that form relatively stable monoesters in biotic systems, which can be further oxidized. The uses of various esters are reviewed below and they vary with the acid. The simple aliphatic esters of benzoic acid are liquids that are used as solvents, flavors, or perfumes. Benzyl benzoate is used as a miticide or as a plasticizer. In general, these compounds have a low order of toxicity. The primary effects expected from the ingestion of moderate amounts of benzoates are gastrointestinal (GI) irritation, gastric pain, nausea, and vomiting. Available data indicate a low order of skin absorbability, and the undiluted materials may be either slight or moderate skin irritants. In rabbits, the degree of skin irritation caused by alkyl benzoates increases with an increase in molecular weight. The salicylates are used as flavorants, perfumes, or analgesics. The most commonly used member of this class of compounds is methyl salicylate. Ingestion of relatively small quantities of methyl salicylate may cause severe, rapid-onset salicylate poisoning. The lower alkyl esters of p- or 4-hydroxybenzoic acid (C1–C4), also named the methyl-, ethyl-, propyl-, and butyl parabens, are high-boiling liquids that decompose on heating. They are widely used in the food, cosmetic, and pharmaceutical industries as preservatives, bacteristats, and fungistats. Parabens also have been used therapeutically in the treatment of moniliasis, a Candida albicans infection. By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The lower paraben homologues have low potential for acute or chronic systemic toxicity and are therefore approved as human food additives. Cinnamates (phenyl acrylates and phenylpropenoic acid esters) are mainly used as fragrances in the perfume industry. Cinnamates appear to have low to moderate toxicity in mammals. In humans, dermal exposure to allyl cinnamate may cause skin irritation. Some p-aminobenzoic acid (PABA) esters occur naturally, because the free compound, PABA, that is utilized for their synthesis, is an intricate part of the vitamin B complex. PABA esters exhibit a low order of acute toxicity in experimental animals. In humans, cases of methemoglobinemia after topical benzocaine or procaine use have been reported. Sunscreen agents containing PABA esters may occasionally produce allergic photosensitization. The o-aminobenzoates (anthranilates) are less irritating and less likely to cause sensitization than do the p-aminobenzoates, but have less therapeutic usefulness. They are used in some sunscreen lotions. Anthranilates have low toxicity potential. Long-chain fatty acids of glycerides may be replaced by one or more acetyl groups to produce mono-, di-, or triacetin. Acetins, propionates, and butyrates serve as food additives, solvents or plasticizers, and surface-active agents. Available evidence indicates that these agents exhibit a low order of toxicity. Normally, no irritant effects occur upon inhalation or direct dermal contact. The higher glycerides of fatty acids with odd-numbered carbon chains (C5–C11) are found naturally in very small quantities in diverse organisms, and the even-numbered (C12–C24) esters are common nutritional constituents. They are used as emulsifiers for foods, industrial raw materials, or nonacid detergent components. Some toxicity data are available for the C5 and C8 compounds. The even-numbered C12–C18 glycerides are nontoxic. Little toxicological information is available about resorcinol ester compounds. Gallates are chemically trihydroxybenzoic acid esters. They serve generally as antioxidants, and the propyl, octyl, and dodecyl gallates have been approved as food additives. The gallates exhibit low acute and chronic toxicity in experimental animals. The bulk of evidence suggests that they are not carcinogenic or teratogenic. Oxalates, malonates, glutarates, and succinates are high-flash, high-boiling fluids. Oxalates and malonates are mainly used as solvents for resins or as chemical intermediates. The general industrial use of these materials has…
The effect of whole cigarette smoke exposure on bone-marrow sister-chromatid exchanges (SCEs) was... more The effect of whole cigarette smoke exposure on bone-marrow sister-chromatid exchanges (SCEs) was studied in B6C3F1 mice. Animals were exposed nose-only to 10% (v/v) cigarette smoke 5 days/week for 2 weeks. Four dose levels of cigarette smoke (1, 4, 9 and 18 exposures/day) were studied using 2 cigarette types, Kentucky reference 3A1 (3A1) and American Blend (AB). A single exposure represented approximately 1 cigarette. A dose-dependent increase in SCEs was observed for both the 3A1 and AB cigarettes at dose levels which had no effect on bone-marrow cell-replication kinetics. These findings represent the first demonstration of a dose-responsive increase in cigarette smoke-induced SCEs in a rodent model system.
Regulatory toxicology and pharmacology : RTP, 2011
In 1998, the National Toxicology Program concluded that inhalation exposure to tetrahydrofuran re... more In 1998, the National Toxicology Program concluded that inhalation exposure to tetrahydrofuran resulted in increased incidences of renal adenomas and carcinomas (combined) in male F344 rats and of hepatocellular adenomas and carcinomas (combined) in female B6C3F1 mice. In the present paper, the bioassay results and additional information are evaluated using the IPCS/ILSI Mode of Action/Human Relevance Framework to determine if the data are sufficient to describe the possible mode(s) of action (MOA) underlying the reported results for the rat renal tumor and to determine if any of these modes of action could be operative in humans. Preliminary analysis of the rat renal tumor data and related information suggested that a MOA could be described, but questions remained concerning the role that chronic progressive nephropathy (CPN) may play in the development of the lesions. In 2009, a Pathology Working Group concluded that the rat renal lesions resulted primarily from regenerative proce...
Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protec... more Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protection Agency (US EPA) for testing under the Multi-Substance Rule for the Testing of Neurotoxicity (US EPA, 1993) using schedule-controlled operant behavior (SCOB) to determine if subchronic exposure to MiBK vapor had the potential to alter behavior as an indicator of neurotoxicity. Food-restricted and ad libitum-fed Sprague-Dawley male rats were exposed to 0, 250, 750, or 1500 ppm MiBK for 6 h/day, 5 d/wk for 13 weeks. SCOB testing of food-restricted animals, using a multiple fixed ratio (FR)/fixed interval (FI) schedule (FR20:FI120), was conducted prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. SCOB testing was also evaluated for two weeks following the cessation of exposures. Ad libitum-fed animals were included to assess systemic effects using routine indicators such as changes in body weight, f...
At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, particip... more At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Rep...
Following oral administration of 1,6-[14C]diaminohexane (hexamethylenediamine, HMDA) to male Fisc... more Following oral administration of 1,6-[14C]diaminohexane (hexamethylenediamine, HMDA) to male Fischer-344 rats, approx. 20% of the administered dose was recovered as 14CO2 after 72 h. Urinary and fecal excretion accounted for 47% and 27% of the administered radioactivity, respectively. Of several tissues examined, the highest concentrations of residual radioactivity were found in the prostate at 24 and 72 h post-administration. Daily administration of HMDA (200 mg/kg/day) by gavage to pregnant female rats for 2 weeks starting on gestation day 0 did not affect litter size in these animals.
Regulatory toxicology and pharmacology : RTP, 2010
Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incide... more Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incidences of renal tumors in male F344/N rats reported in a 2-year carcinogenicity study by the National Toxicology Program (NTP). A Pathology Working Group (PWG) was commissioned to conduct an independent review of the kidney slides from this bioassay (along with two subchronic studies) to assess renal changes in light of recent scientific work on pathogenesis of pre-neoplastic and neoplastic lesions in rat kidney. PWG pathologists confirmed the NTP assessment that adenomas were non-statistically increased in animals exposed to the highest level of THF. However, when pre-neoplastic and neoplastic lesions were combined, there was no difference between control and THF-exposed groups. Also, the majority of these proliferative lesions were in rats with severe chronic progressive nephropathy (CPN). Accordingly, the PWG concluded that renal lesions in the control and THF-exposed groups resulted pr...
BACKGROUND: The plasticizer di-2-ethylhexyl phthalate (DEHP) is a common component in medical pla... more BACKGROUND: The plasticizer di-2-ethylhexyl phthalate (DEHP) is a common component in medical plastics. There is motivation to replace this component; however, DEHP is necessary to prevent excessive hemolysis in stored red blood cells (RBCs). Our objective is to evaluate a candidate replacement plasticizer (Hexamoll, di-isononyl cyclohexane-1,2-dicarboxylic acid [DINCH], BASF Corp.) compared to DEHP in an in vitro feasibility study. We hypothesize that the candidate will provide at least equivalent protection against hemolysis for RBCs stored for 42 days and periodic mixing of RBCs will add additional protection against hemolysis. STUDY DESIGN AND METHODS: Whole blood was collected into citrate-phosphate-dextrose; combined into pools of 2 ABO identical whole blood units; and divided, leukoreduced, centrifuged, and separated into plasma and RBCs. Additive solution was added, and the RBCs were stored for 42 days at 1 to 6°C. In three parts of this study, split pools were paired as DINCH-polyvinyl chloride (PVC) with weekly mixing versus DINCH-PVC with no mixing, DINCH-PVC mixed versus DEHP-PVC no mix, and DINCH-PVC versus DEHP-PVC with neither mixed. A standard panel of in vitro RBC characteristics was determined on Days 0 and 42. RESULTS: Mixing DINCH-PVC weekly improved Day 42 hemolysis (0.36 Ϯ 0.07% vs.0.56 Ϯ 0.15%, p = 0.002), and mixed DINCH-PVC bags were noninferior to unmixed DEHP-PVC bags (p Յ 0.05). DINCH-PVC bags stored without weekly mixing were inferior to unmixed DEHP-PVC bags for hemolysis on Day 42, although no individual bag exceeded 0.8% hemolysis. CONCLUSION: Periodic mixing of RBCs stored in DINCH-PVC provides additional protection against hemolysis. Unmixed DINCH-PVC bags were inferior to DEHP-PVC bags for prevention of hemolysis, but remain a candidate for replacement DEHP in RBC storage bags. ABBREVIATIONS: BTHC = n-butyl tri-n-hexyl citrate; DEHP = di-2-ethylhexyl phthalate; DINCH = di-isononyl cyclohexane-1,2-dicarboxylic acid; LOQ = limits of quantification; MCV = mean corpuscular volume; MINCH = mono-isononyl-1,2cyclohexane dicarboxylic acid.
Bronchial asthma is mediated, in part, by the immunoregulatory cytokines interleukins 4 and 13 (I... more Bronchial asthma is mediated, in part, by the immunoregulatory cytokines interleukins 4 and 13 (IL-4 and IL-13). These cytokines stimulate IgE synthesis that in turn is associated with airway hyper-responsiveness. Compounds that stimulate IgE synthesis and elicit bronchial reactivity are generally considered to be respiratory sensitizers. Recently, it has been hypothesized that exposure to phthalates may contribute to childhood asthma. To address this question, di-(2-ethylhexyl) phthalate (DEHP) was tested using a protocol adapted from work by Dearman that involves topical application (and challenge) of test substances to mice followed by measurements of total serum IgE. In addition, auricular lymph nodes were harvested for measurement of IL-4 and IL-13 proteins and their corresponding messenger RNAs. Because skin absorption of high molecular weight phthalates is limited, liver weight increase, a measure of peroxisomal proliferation, was monitored to assure that internal dosing had been achieved. ELISA and RNAse protection assays demonstrated that DEHP treatment did not significantly affect IgE, IL-4, or IL-13 levels. Similarly, IL-4 and IL-13 mRNA levels were not elevated. In contrast, all of these were significantly elevated by trimellitic anhydride (TMA), a respiratory sensitizer used as the positive control in this assay. Liver weights were significantly elevated by DEHP, providing evidence of sufficient percutaneous absorption to induce physiological responses. To extend these observations, three other commercial phthalate ester plasticizers, di-isononyl phthalate (DINP), di-isohexyl phthalate (DIHP), and butyl benzyl phthalate (BBP), were assessed using the same protocol. As above, ELISA and RNAse protection assays showed that IgE, IL-4, and IL-13 proteins, and IL-4 and IL-13 mRNAs in the phthalate-treated animals were all at levels similar to that of control values. The positive control, TMA, produced large, statistically significant increases in all parameters, demonstrating responsiveness of the assay. Another control, dinitrochlorobenzene (DNCB), a contact sensitizer, also responded as expected, producing smaller but statistically significant increases in IgE and in mRNA for IL-4 and IL-13 but not in the levels of these cytokines.
Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm di(2-ethylhexyl)phthalate (DE... more Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at weeks 26, 52, 78, and 104 from 10 animals per sex per group. Survival was slightly but not statistically reduced for rats receiving 12,500 ppm DEHP. Body weights and food consumption were significantly reduced for rats receiving the highest dose level of DEHP and occasionally for the male 2500-ppm group. BUN and albumin were significantly higher and globulin lower at nearly every sampling interval for the 12,500-ppm group compared with the controls. There was an increase in the mean activities of AST and ALT at 104 weeks, but no statistically significant differences were seen. Erythrocyte count, hemoglobin, and hematocrit values for the 12,500-ppm group were significantly lower than controls at nearly every sampling interval. No other differences in hematology were seen. No toxicologically significant changes were observed in urinalysis. At termination, relative lung weights for the 2500-and 12,500-ppm male groups of rats were significantly higher than for the controls. Absolute and relative liver and kidney weights for the 2500-and 12,500-ppm male rats, and liver weights for 12,500-ppm female rats were higher compared with the controls. Absolute and relative testes weights for the 12,500-ppm male rats were lower compared with the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately and correlated with the induction of peroxisomal enzyme activity (David et al., 1999). A dose level of 500 ppm was the NOEL for peroxisome proliferation. Bilateral aspermatogenesis in the testes, castration cells in the pituitary gland, spongiosis hepatis, and pancreatic acinar cell adenoma were observed for 12,500ppm male rats. Aspermatogenesis and spongiosis hepatis were observed for 2500-ppm male rats, and aspermatogenesis was seen at 500 ppm. DEHP exposure exacerbated age-, species-or strainrelated lesions such as mineralization of the renal papilla and chronic progressive nephropathy in male rats. Kupffer cell pigmentation and renal tubule pigmentation were seen in male and female 12,500-ppm rats. The increased incidence of spongiosis hepatis correlated with increased palmitoyl CoA oxidase activity, but the incidence of pancreatic acinar cell adenoma was increased only at the highest dose level of 12,500 ppm. These lesions, although typical of those seen with other peroxisome proliferators, may respond differently depending on the potency of the peroxi-some proliferator. A dose level of 500 ppm (28.9-36.1 mg/kg/day) was considered to be theNOAEL.
This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver... more This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver with tumor incidence, to provide more information on the relationship between these events following chronic exposure. Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm DEHP, and B6C3F 1 mice were treated with 0, 100, 500, 1500, or 6000 ppm DEHP in the diet for up to 104 weeks. Additional groups of rats and mice received the highest concentration for 78 weeks and then the control diet for an additional 26 weeks (recovery groups). Animals were terminated at weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA oxidation activity and higher liver-to-body weight ratios were observed for the 2500-and 12,500-ppm groups of rats, and for the 500-, 1500-, and 6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation activity was evident in the recovery group, and relative liver weights were near control levels following recovery. No hepatic cell proliferation was detected at Weeks 79 or 105 in either species although preliminary data indicated that cell proliferation did occur within the first 13 weeks of exposure. A significantly higher incidence of hepatocellular tumors was only observed for the 2500-and 12,500-ppm group and its recovery group of rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group of mice. The tumor incidences were reduced for the recovery groups compared with the groups fed DEHP continuously for 104 weeks. The data indicate that high levels of peroxisome proliferation and hepatomegaly are associated with DEHP hepatocarcinogenesis in rodent liver, and that the tumorigenic process may be arrested by cessation of DEHP treatment, suggesting that extended treatment with DEHP acts to promote tumor growth.
Fischer-344 rats treated with 12,500 ppm (728 and 879 mg/kg/d for male and females, respectively)... more Fischer-344 rats treated with 12,500 ppm (728 and 879 mg/kg/d for male and females, respectively) and B6C3F1 mice treated with 6,000 ppm (1,227 and 1,408 mg/kg/d, respectively) di(2-ethylhexyl)phthalate (DEHP) in the diet for 78 weeks were allowed to recover for an additional 26 weeks on control diet. Blood was analyzed at weeks 78 and 104 from 10 animals per sex per group; animals were sacrificed at weeks 79 and 105 for histopathologic examination. The results are compared with data from animals continuously exposed to these dietary levels for 104 weeks (10, 11). Body weights and food consumption were measured monthly. BUN, albumin, and globulin that were significantly different for rats exposed to DEHP throughout 104 weeks, were comparable to controls for the recovery group. Reversibility of chronic effects on erythrocyte count, hemoglobin, and hematocrit values was apparent only for female rats. Chronic exposure demonstrated effects on liver, kidney, and testes weights. All organ...
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